rs143948820

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP6_Very_StrongBS1BS2_Supporting

The NM_000371.4(TTR):c.*3_*11delGACTTCTCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,614,064 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00064 ( 7 hom. )

Consequence

TTR
NM_000371.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.968

Publications

1 publications found

Variant links:

Genes affected

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

TTR Gene-Disease associations (from GenCC):

amyloidosis, hereditary systemic 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
familial amyloid neuropathy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary ATTR amyloidosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
heart conduction disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
ATTRV122I amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TTR links:

ENSG00000294516 (HGNC:):

ENSG00000294516 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP6

Variant 18-31598677-GGACTTCTCC-G is Benign according to our data. Variant chr18-31598677-GGACTTCTCC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00106 (162/152276) while in subpopulation EAS AF = 0.0238 (123/5174). AF 95% confidence interval is 0.0204. There are 2 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 162 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4 link	c.3_11delGACTTCTCC		3_prime_UTR_variant	Exon 4 of 4	ENST00000237014.8	NP_000362.1	P02766E9KL36
LOC124904277	XR_007066326.1 link	n.129-2991_129-2983delGGAGAAGTC		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTR	ENST00000237014.8 link	c.3_11delGACTTCTCC	3_prime_UTR_variant	Exon 4 of 4	1	NM_000371.4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1 link	c.3_11delGACTTCTCC	3_prime_UTR_variant	Exon 6 of 6			ENSP00000497927.1	P02766
TTR	ENST00000610404.5 link	c.3_11delGACTTCTCC	3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000477599.2	A0A087WT59
ENSG00000294516	ENST00000724044.1 link	n.286-2991_286-2983delGGAGAAGTC	intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

159

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0235

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00214

AC:

539

AN:

251372

AF XY:

0.00216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0266

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000642

AC:

938

AN:

1461788

Hom.:

AF XY:

0.000649

AC XY:

472

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0178

AC:

708

AN:

39696

South Asian (SAS)

AF:

0.000997

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111958

Other (OTH)

AF:

0.00222

AC:

134

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00106

AC:

162

AN:

152276

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41564

American (AMR)

AF:

0.00137

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0238

AC:

123

AN:

5174

South Asian (SAS)

AF:

0.00187

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.00149

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP6 -

Oct 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

*3_*11del in the 3' UTR of TTR: This variant is not expected to have clinical si gnificance because it has been identified in 2.8% (16/572) of Asian chromosomes from a broad population by the 1000 Genomes project (dbSNP rs143948820). *3_*1 1del in the 3' UTR of TTR (rs143948820; allele frequency = 2.8%, 16/572) -

not provided

Benign:3

Dec 06, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The TTR c.*3_*11delGACTTCTCC variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in 253/121230 control chromosomes (5 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.0262914 (227/8634). This frequency is about 841 times the estimated maximal expected allele frequency of a pathogenic TTR variant (0.0000313), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

May 24, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Apr 28, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 04, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.97

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over